Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells

Background

Neuroblastoma (NB) is one of the most common childhood malignancies. Currently, high risk NB carries a poor outcome and significant treatment related toxicities and, thus has been a focus for new therapeutics research in pediatric oncology. In this study, we evaluated the effects of the MEK inhibitor cobimetinib, as a single agent and in combinations, on the growth, survival and differentiation properties against a molecularly representative panel of NB cell lines.

Methods

In vitro anti-proliferative activity of cobimetinib alone or in combination was investigated by cell viability assays and its target modulatory activity was evaluated using phospho-kinases antibody arrays and western blot analysis. To determine the effect of combination with cis-RA on differentiation and resulting enhanced cellular cytotoxicity, the expression of glial fibrillary acidic protein (GFAP) and microtubule-associated protein 2 (MAP2) expression levels were examined by immuno-fluorescence.

Results

Our findings show that cobimetinib alone induced a concentration-dependent loss of cell viability in all NB cell lines. In addition, cobimetinib showed feedback activation of MEK1/2, and the dephosphorylation of extracellular signal-regulated kinases (ERK1/2) and c-RAF, providing information on the biological correlates of MEK inhibition in NB. Combined treatment with cis-RA, led to differentiation and enhanced sensitization of NB cells lines to cobimetinib.

Conclusion

Collectively, our results provide evidence that cobimetinib, in combination with cis-RA, represents a feasible option to develop novel treatment strategies for refractory NB.     

Dental attendance patterns in renal transplant recipients

OBJECTIVES: Renal transplant recipients (RTR) represent a large and growing population of individuals on potent immunosuppressant therapy who are at significantly greater risk of developing lip and oral mucosal disease, including lip cancer. The aims of this study were to determine the proportion of RTR receiving regular dental treatment, the dental services they used, and the relationship between the prevalence of lip and intraoral lesions and dental attendance.
DESIGN: The lip and oral mucosa of 159 RTR and 160 controls were examined. Subjects were asked questions about frequency of dental attendance and which service they used.
RESULTS: 57.9% RTR attended a dentist regularly compared with 51.3% controls. Among the RTR who attended a dentist regularly, 54.3% visited their general dental practitioner, and 45.6% attended a dental hospital for treatment. This was significantly different from controls where 92.7% of regular attenders used their general dental practitioner (P<0.001). Although the prevalence of oral lesions in RTR (54.7%) was more than twice as many as controls (19.4%). no significant difference was observed between RTR regular dental attenders and non-attenders.
CONCLUSIONS: This study indicates a clear need for oral health care and screening to be focused on RTR.     

Mice lacking G0S2 are lean and cold-tolerant

G₀/G₁ switch gene 2 (G0S2) is a protein that was first identified in a search for lymphocyte G₀/G₁ switch genes. A direct role for G0S2 in cell cycle regulation has proven elusive. Yet, there is prior evidence for G0S2 functioning in tumor suppression, immune regulation and lipolysis. To explore definitively G0S2 functions, mice lacking G0S2 were generated and characterized. G0S2^−/− mice were born at a Mendelian ratio and were phenotypically normal, with the exception of a possible lactation defect. G0S2^−/− female mice carried viable pups to term, but could not typically sustain them beyond 48 h. G0S2 is shown here to be most highly expressed in adipose tissue. It is also expressed in liver, skeletal muscle, lung, ventricles of the heart, and components of the kidney. G0S2 loss significantly decreased relative body weight gain as compared with wild-type (WT) (G0S2^+/+) mice, with a significant decrease in gonadal fat pad weight and a significant increase in serum glycerol levels. This decreased relative body weight gain is not associated with a significant decrease in food intake or increase in activity of G0S2^−/− mice. In fact, G0S2^−/− mice were significantly less active at night than G0S2^+/+ mice. When fed with a high fat diet (45% fat diet), G0S2 loss did not prevent diet-induced obesity in mice. Intriguingly, G0S2 loss improved acute cold tolerance, augmenting expression of genes involved in thermogenesis. In summary, in vivo roles for G0S2 were found in lactation, energy balance, and thermogenesis. This study provides a basis for tumor suppressive effects of G0S2 by regulating lipolysis.     

基质金属蛋白酶及其组织抑制剂在结膜松弛症成纤维细胞中的表达

目的探讨基质金属蛋白酶1、3（MMP．1、MMP．3）及其组织抑制因子1、3（TIMP-1、TIMP．3）在结膜松弛症（CCh）成纤维细胞培养上清液中的表达,揭示四者表达水平变化与CCh的内在联系。方法体外原代培养CCh成纤维细胞,取第3—6代细胞,以2．5×10^5个／mL浓度接种于24孔板中培养,24h后提取细胞上清液,采用ELISA检测MMP-1、MMP-3、TIMP-1、TIMP-3的表达水平。不同组间比较采用单因素方差分析。结果MMP-1的表达：CCh组成纤维细胞的蛋白浓度明显高于正常对照组,差异有统计学意义（P〈0．05）。MMP-3的表达：CCh组成纤维细胞的蛋白浓度明显高于正常对照组,差异有统计学意义（P〈0．01）。TIMP．1的表达：CCh组成纤维细胞的蛋白浓度与正常对照组比较,差异无统计学意义（P〉0．05）。TIMP-3的表达：CCh组成纤维细胞的蛋白浓度明显低于正常对照组,差异有统计学意义（P〈0．05）。结论成纤维细胞MMP．1／TIMP-1及MMP-3／TIMP-3的表达失衡可能参与了CCh的发生、发展。     

Duodenocaval fistula from inferior vena cava filter penetration masquerading as lower gastrointestinal bleeding

Asymptomatic penetration of the inferior vena cava (IVC) wall with retrievable filters is not uncommon. Occasionally, this can be a cause for morbidity, and rarely for mortality. We present a case of duodenocaval fistula, secondary to penetration from a strut of retrievable IVC filter that presented as lower gastrointestinal bleeding and discuss the subsequent management. Although newer generation retrievable filters provide a longer time for retrieval, they are associated with an increased incidence of IVC wall penetration, caudal migration, and occasionally symptomatic presentation, thereby necessitating surgical intervention. Close follow-up is warranted, and prompt retrieval of such devices should be done when their use is no longer indicated.     

Oxidized phospholipids reduce ventilator-induced vascular leak and inflammation <Emphasis Type="Italic">in vivo</Emphasis>

Background  

Mechanical ventilation at high tidal volume (HTV) may cause pulmonary capillary leakage and acute lung inflammation resulting in ventilator-induced lung injury. Besides blunting the Toll-like receptor-4-induced inflammatory cascade and lung dysfunction in a model of lipopolysaccharide-induced lung injury, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) exerts direct barrier-protective effects on pulmonary endothelial cells in vitro via activation of the small GTPases Rac and Cdc42. To test the hypothesis that OxPAPC may attenuate lung inflammation and barrier disruption caused by pathologic lung distension, we used a rodent model of ventilator-induced lung injury and an in vitro model of pulmonary endothelial cells exposed to pathologic mechanochemical stimulation.